Evaluation of the Impact of Comorbidities on Omadacycline Pharmacokinetics.

Omadacycline is approved in the United States for the treatment of patients with community-acquired bacterial pneumonia or acute bacterial skin and skin structure infections. Analyses were undertaken to evaluate pharmacokinetic differences among subjects or patients stratified by comorbidities. Differences in clearance by smoking status, history of diabetes mellitus, chronic lung disease, hypertension, heart failure, or coronary artery disease were evaluated using a Welch two-sample t test. Smoking was the only significant comorbidity after correction for sex, with a clinically insignificant difference of 13%. Omadacycline dose adjustments based on these comorbidities do not appear to be warranted.

A pilot study of high-dose short duration daptomycin for the treatment of patients with complicated skin and skin structure infections caused by gram-positive bacteria.

BACKGROUND: Methicillin-susceptible and -resistant (MRSA) Staphylococcus aureus are significant causes of complicated skin and skin structure infections (cSSSI). The bactericidal antibiotic daptomycin is approved for gram-positive cSSSI at 4 mg/kg/day for 7-14 days, but the optimal dose level and duration of therapy have not been firmly established. This pilot study evaluated the efficacy and safety of daptomycin at 10 mg/kg every 24 h for 4 days [high-dose short duration (HDSD) regimen] vs. standard of care therapy with vancomycin or semi-synthetic penicillin for the treatment of cSSSI. METHODS: This was a semi-single blind, randomised, multicentre, comparative trial. The primary efficacy end-point was the clinical response 7-14 days posttherapy. RESULTS: One hundred patients were randomised; 48 in each arm were treated. The treatment groups were well balanced with respect to demographics, comorbidities and the type of infection (75% because of MRSA). Overall, clinical success rates were 75.0% (36/48) for daptomycin and 87.5% (42/48) for comparator (95% confidence interval for the difference: -27.9, 2.9). The median duration of comparator therapy was 8 days. Two comparator patients and no daptomycin patients experienced treatment-related serious adverse events requiring hospitalisation. CONCLUSION: We found that the HDSD regimen had a safety profile similar to that seen in previous studies. Although the differences were not statistically significant, clinical success rates for comparator were higher than for daptomycin. In post hoc analyses HDSD daptomycin performed better in some subgroups (e.g. outpatients) than in others (e.g. certain MRSA infections). These observations require confirmation in larger trials.

Cryptococcus neoformans interactions with amoebae suggest an explanation for its virulence and intracellular pathogenic strategy in macrophages.

Cryptococcus neoformans (Cn) is a soil fungus that causes life-threatening meningitis in immunocompromised patients and is a facultative intracellular pathogen capable of replication inside macrophages. The mechanism by which environmental fungi acquire and maintain virulence for mammalian hosts is unknown. We hypothesized that the survival strategies for Cn after ingestion by macrophages and amoebae were similar. Microscopy, fungal and amoebae killing assays, and phagocytosis assays revealed that Cn is phagocytosed by and replicates in Acanthamoeba castellanii, which leads to death of amoebae. An acapsular strain of Cn did not survive when incubated with amoebae, but melanization protected these cells against killing by amoebae. A phospholipase mutant had a decreased replication rate in amoebae compared with isogenic strains. These observations suggest that cryptococcal characteristics that contribute to mammalian virulence also promote fungal survival in amoebae. Intracellular replication was accompanied by the accumulation of polysaccharide containing vesicles similar to those described in Cn-infected macrophages. The results suggest that the virulence of Cn for mammalian cells is a consequence of adaptations that have evolved for protection against environmental predators such as amoebae and provide an explanation for the broad host range of this pathogenic fungus.

Prevalence of Cryptococcus neoformans var. neoformans (Serotype D) and Cryptococcus neoformans var. grubii (Serotype A) isolates in New York City.

Analysis of 40 New York City Cryptococcus neoformans isolates revealed that 39 were typeable, of which 85 and 12.5% were Cryptococcus neoformans var. grubii (serotype A) and Cryptococcus neoformans var. neoformans (serotype D), respectively. The prevalence of serotype D isolates in New York City appears to be significantly higher than indicated by previous studies of North American isolates.

Genetic study of interactions between the cytoskeletal assembly protein sla1 and prion-forming domain of the release factor Sup35 (eRF3) in Saccharomyces cerevisiae.

Striking similarities between cytoskeletal assembly and the "nucleated polymerization" model of prion propagation suggest that similar or overlapping sets of proteins may assist in both processes. We show that the C-terminal domain of the yeast cytoskeletal assembly protein Sla1 (Sla1C) specifically interacts with the N-terminal prion-forming domain (Sup35N) of the yeast release factor Sup35 (eRF3) in the two-hybrid system. Sla1C and several other Sup35N-interacting proteins also exhibit two-hybrid interactions with the poly-Gln-expanded N-proximal fragment of human huntingtin, which promotes Huntington disease-associated aggregation. The Sup35N-Sla1C interaction is inhibited by Sup35N alterations that make Sup35 unable to propagate the [PSI(+)] state and by the absence of the chaperone protein Hsp104, which is essential for [PSI] propagation. In a Sla1(-) background, [PSI] curing by dimethylsulfoxide or excess Hsp104 is increased, while translational readthrough and de novo [PSI] formation induced by excess Sup35 or Sup35N are decreased. These data show that, in agreement with the proposed function of Sla1 during cytoskeletal formation, Sla1 assists in [PSI] formation and propagation, but is not required for these processes. Sla1(-) strains are sensitive to some translational inhibitors, and some sup35 mutants, obtained in a Sla1(-) background, are sensitive to Sla1, suggesting that the interaction between Sla1 and Sup35 proteins may play a role in the normal function of the translational apparatus. We hypothesize that Sup35N is involved in regulatory interactions with intracellular structural networks, and [PSI] prion may be formed as a by-product of this process.

Molecular and genetic analysis of iron uptake proteins in the brazilian purpuric fever clone of Haemophilus influenzae biogroup aegyptius.

Haemophilus influenzae biogroup aegyptius (H. aegyptius) is the etiological agent of Brazilian purpuric fever (BPF), a recently described pediatric disease that is often fatal. The vascular destruction that occurs in this disease is a distinctive trait, and little is known about the mechanism(s) of the overwhelming purpura fulminans that causes the high mortality associated with this pediatric infection. Iron is an essential micronutrient for nearly all living cells, and the mechanisms used by bacteria to acquire and internalize iron are often associated with virulence. Therefore, the focus of our studies is the molecular characterization of the iron uptake system used by H. aegyptius. Specifically, we are investigating the high-affinity transferrin binding proteins in the bacterial outer membrane, components of ABC transporter systems, and a possible regulatory mechanism for the genes encoding these proteins. A detailed understanding of the molecular nature of the regulatory genetic components and proteins involved in the acquisition of iron will broaden the knowledge of the pathogenesis of the disease caused by H. aegyptius and will also lead to a better understanding of the nature of other infections that affect the vascular system.